Early N-terminal pro-B-type natriuretic peptide is associated with cardiac complications and function during pregnancy in congenital heart disease.

BACKGROUND: Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at 20 weeks' gestation predict adverse cardiovascular (CV) complications during pregnancy in women with congenital heart disease (CHD). To improve early risk assessment in these women, we investigated the predictive value of first-trimester NT-proBNP for CV complications and its association with ventricular function during pregnancy. METHODS: Pregnant women with CHD, previously enrolled in a prospective national study or evaluated by an identical protocol, were included. Clinical data, echocardiographic evaluation and NT-proBNP measurements were obtained at 12, 20 and 32 weeks' gestation. Elevated NT-proBNP was defined as > 235 pg/ml (95th percentile reference value of healthy pregnant women in the literature). RESULTS: We examined 126 females (mean age 29 years). Elevated NT-proBNP at 12 weeks was associated with CV complications (n = 7, 5.6%, odds ratio 10.9, p = 0.004). Arrhythmias were the most common complication (71%). The negative predictive value of low NT-proBNP to exclude CV complications was 97.2%. In women with CV complications, NT-proBNP levels remained high throughout pregnancy, while a decrease was seen in women without CV complications (p < 0.001 for interaction between group and time). At 12 weeks, higher NT-proBNP levels were associated with impaired subpulmonary ventricular function (p < 0.001) and also with a decline in subpulmonary ventricular function later in pregnancy (p = 0.012). CONCLUSIONS: In this study, first-trimester NT-proBNP levels were associated with adverse CV complications and a decline in subpulmonary ventricular function later in pregnancy in women with CHD. Early NT-proBNP evaluation is useful for tailored care in pregnant women with CHD.

(2,6-Methano-3-benzazocin-11 beta-yl)alkanones. 1. Alkylalkanones: a new series of N-methyl derivatives with novel opiate activity profiles.

A general stereospecific synthesis of (N-methyl-2,6-methano-3-benzazocin-11 beta-yl)alkanones is described and applied to the preparation of a series of alkyl ketones wherein the alkyl group is a straight or terminally branched chain containing from one to six carbon atoms. Several compounds with methoxy groups in the aromatic ring are in the morphine range of potency; they are uniformly inactive as phenazocine antagonists. Phenolic analogues range up to 100 times as potent as morphine. Those containing five or six carbon atoms in the alkyl group exhibit phenazocine antagonist activity, in one case equivalent to naloxone. This compound (3e) is selective for phenazocine in its antagonist action.

Drugs derived from cannabinoids. 1. Nitrogen analogs, benzopyranopyridines and benzopyranopyrroles.

Various nitrogen analogs of delta6a,10a-tetrahydrocannabinol were synthesized by a general procedure described in an earlier communication. Minimum effective doses (MED50's) and lethal doses (LD50's) were determined by a modified Irwin mouse screen after iv administration of compounds in PEG 200. The most potent compounds were the propargyl (5t), allyl (5m), and chloroallyl (5o-q) derivatives. Overt behavioral effects (CNS depression, static ataxia, and hypersensitivity) of 5t and Roger Adams' carbocyclic analog (III) were found to be similar in the mouse, cat, dog, and monkey. Dichloroisoproterenol prevented and reversed many of the depressant effects of both III and 5t but had no effect on the ataxia produced by these compounds. In antinociceptive tests, 5t was active in the phenylquinone and Eddy hot-plate tests but was inactive in the tail-flick test.

Emetic activity of N-substituted norapomorphines.

Norapomorphine and ten of its N-substituted derivatives were prepared by modifications of procedures described earlier. In a dog emesis test the N-ethyl and N-n-propyl compounds had minimum effective doses of 0.00025 and 0.0005 mg/kg, respectively, when administered iv, sc, or im. In a modified Irwin mouse profile screen the minimum effective iv dose was 0.013 mg/kg for the N-ethyl and 0.0024 mg/kg for the N-n-propyl compound; percutaneous absorption was also observed in mice. All compounds examined caused the stereotyped apomorphine behavior syndrome but hypotensive effects were not serious.

Dual effects of aspirin in guinea-pig lungs.

Dual effects of aspirin were demonstrated in guinea-pig lungs: (a) aspirin (3.3 mg/kg i.v.) antagonized bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS-A); (b) aspirin produced bronchoconstriction when injected in the presence of propranolol into guinea-pigs in vivo at 330 mg/kg, or into guinea-pig isolated lungs in vitro as a 4% solution (40 mg/ml). 2 The severity of bronchoconstriction following administration of aspirin was directly related to the degree of beta-adrenoceptor blockade and to the age of the guinea-pigs. Aspirin-induced bronchoconstriction was prevented in vivo and in vitro by atropine and it could be reversed in vivo by atropine. Aspirin-induced bronchoconstriction was not inhibited by vagotomy or phenoxybenzamine. 3 These data suggest that the mechanism involved in aspirin-induced bronchoconstriction may be local cholinergic stimulation and that reduced beta-adrenergic drive may be a predisposing factor.

Steroid-responsive pleuropericarditis and livedo reticularis in an unusual case of adult-onset primary hyperoxaluria.

We present a case of a 54-year-old woman with rapidly progressive renal failure of uncertain origin, who developed pleuropericarditis and livedo reticularis 6 weeks after initiation of hemodialysis (HD). The presentation with acute renal failure, the development of serositis, and the dramatic clinical response to empiric steroid therapy initially suggested the diagnosis of a systemic inflammatory disorder or vasculitis. Renal biopsy, performed 3 days after presentation, suggested crystal deposition disease, and subsequent investigations, using both dialysate oxalate concentrations and liver biopsy, led to the diagnosis of primary hyperoxaluria (PH). We discuss this atypical adult presentation of PH and propose a role for the use of steroids in the management of the acute inflammatory symptoms of oxalosis. We also briefly discuss the current medical management of patients with PH, including transplantation.

Intrathecal tolerance of metrizamide in chloralose anesthetized cats.

The water soluble radiopaque medium, metrizamide (Amipaque) was introduced into the lumbar subarachnoid space in chloralose anesthetized cats at a standard volume of 0.35 cc/kg in concentrations of 300 mgI/cc to 500 mgI/cc during EMG recording. These animals did not differ from controls which received cerebrospinal fluid under otherwise identical conditions; both groups usually showed some mild and occasional muscle fasciculations or mild spasms. Treatment with metrizamide appeared to be a less deleterious procedure than that using hyperosmotic sucrose (1.32 M) as judged from EMG records. In contrast, equivalent amounts of neglumine iothalamate produced frank convulsions in 7 of 15 cases and a range of hyperirritability in the remaining 8.

Iosulamide: a new intravenous cholangiocholecystographic medium.

Iosulamide is a bis-benzoic analogue of metrizoate that shows clear advantages in animal tests over meglumine iodipamide. The intravenous toxicity of iosulamide meglumine is considerably lower than that of iodipamide (Cholografin) in the mouse and rat. The LD50 in mice for iosulamide meglumine is 11,500 +/- 844 mg free acid/kg and for iodipamide is 2380 +/- 290 mg free acid/kg. A threefold difference in toxicity was seen in rats; the LD50 for iosulamide meglumine is 13,600 +/- 1710 mg free acid kg and for iodipamide is 4430 +/- 310 mg free acid/kg. Iosulamide is a highly effective contrast agent for cholangiocholecystographic visualization in cats and monkeys. speed and degree of opacification are equivalent to that of iodipamide at equimolar doses. Studies of biliary and urinary excretion patterns indicate iosulamide is rapidly excreted compared to iodipamide, while at the same time providing equal concentrations in bile on an mg/ml bile basis. A more efficient blood to bile clearance rate and a shorter blood half-life for iosulamide may account for the lower circulating blood levels and rapid total excretion compared to iodipamide. Iosulamide's rapid blood-bile clearance coupled with its extremely low toxicity may allow rapid administration of high doses, affording superior visualization and safety compared to iodipamide. It may also provide visualization of the liver parenchyma with computerized axial tomography, due to the pharmacokinetic profile that provides for high liver clearance but low blood levels. The emetic potential of iosulamide meglumine is quite low compared to iodipamide. Iosulamide meglumine also lacks hypotensive activity. Little or no effect on blood pressure was seen with iosulamide meglumine in cats or monkeys, whereas iodipamide caused marked transient, or sustained, reductions. Iosulamide meglumine did not produce significant toxic effects when administered as single daily intravenous injections to albino rats for three weeks, or in 10-minute intravenous infusions to rhesus monkeys 10 times in 14 days. Clinical trials with iosulamide are under way.

Metrizamide, iothalamate, and metrizoate: effects of internal carotid arterial injections on the blood-brain barrier of the rabbit.

Experiments were conducted on anesthetized rabbits to determine the effect of internal carotid artery injection of various contrast media on permeability changes in the blood-brain barrier. Changes in respiratory pattern, neuromuscular effects, and trypan blue extravasation were recorded after 3-ml injections of ionic and nonionic contrast media. Metrizamide and iothalamate meglumine were compared at iodine doses of 300, 400, and 500 mg I/ml. Metrizoate at 280 and 440 mg I/ml and diatrizoate meglumine at 385 mg I/ml were also included for comparison. The results demonstrated that metrizamide at all three iodine concentrations used caused minimal disruption of the blood-brain barrier, the effect being no greater, statistically, than saline controls. Iothalamate was benign at the lowest iodine concentration, but caused significant barrier breakdown at the two higher concentrations. These results suggest that alterations in blood-brain barrier permeability following angiography are mediated by both hyperosmolality of the contrast medium and the chemotoxicity of the contrast molecule.

Plasma ionized calcium and blood lactate concentrations are inversely associated in human lactic acidosis.

Plasma ionized calcium [Ca++] concentrations are decreased in patients having lactic acidosis. To further investigate this observation, we prospectively studied nine critically ill patients who had lactic acidosis and measured arterial pH, PCO2, [Ca++], lactate, and albumin concentrations. We found a strong association between decreased [Ca++] and increased plasma lactate concentrations (r2 = 0.78, p less than or equal to 0.001). This unexpected association--[Ca++] usually increases with increasing acidosis--might be clinically important and the mechanism deserves further investigation.

Pemphigus: a 20-year review of 107 patients treated with corticosteroids.

We review 107 consecutive cases of pemphigus. The mortality for pemphigus vulgaris and pemphigus vegetans was 46% between 1949 and 1959 and 24% between 1960 and 1970. The overall mortality for all types of pemphigus was 32%. In the corticosteroid era, complications of therapy were the most frequent causes of death. Mortality and morbidity closely correlated with the corticosteroid dosage used to attain control. This dosage proved to be variable and could not be predicted at the outset in any given patient.

Differential effects of various secretagogues on quantal transmitter release from mouse motor nerve terminals treated with botulinum A and tetanus toxin.

Electrophysiological and electron microscopic techniques were used to investigate the actions of potassium depolarization, black widow venom (BWSV), Ca2+-ionophore A 23187 and hyperosmotic solution on mouse hemidiaphragms poisoned in vitro with botulinum A toxin (BoTx) and tetanus toxin (TeTx). These neurotoxins reduced the frequency of miniature endplate potentials (m.e.p.ps) from 5/s of the control to 2/min and 21/min, respectively. High potassium (25 mmol/l) increased the m.e.p.p.-frequency at BoTx- and TeTx-poisoned endplates to 30/min and 50/s, respectively. The ultrastructure of endplates showed no obvious changes. BWSV (0.04 glands/ml) was just as effective in promoting transmitter release from BoTx-treated endplates as in control preparations. Electron micrographs revealed depletion of vesicles as well as swollen and disrupted mitochondria. When preparations were pretreated with TeTx, BWSV only moderately increased transmitter release and no alterations of the ultrastructure could be observed. At TeTx- or BoTx-poisoned endplates Ca2+-ionophore A 23187 usually produced an extreme reduction of m.e.p.p.-frequency (0.005/s), sometimes preceded by a short burst-like release. The ultrastructure of these endplates was not obviously affected. Application of hyperosmotic solution to BoTx- or TeTx-poisoned preparations further reduced the already low m.e.p.p.-frequency. These results further demonstrate that TeTx and BoTx act at different sites in the transmitter releasing process.

Microencapsulation of bitolterol for controlled release and its effect on bronchodilator and heart rate activities in dogs.

Spheronized cores produced by extrusion and marumerization were microencapsulated with ethylcellulose by organic phase separation to produce beads exhibiting controlled-release characteristics. In vitro dissolution studies indicated that the drug was released as a first-order model and that the release rates were proportional to the amount of film on the bead. The bronchodilator activity in the anesthetized dog and the heart rate effect in the unanesthetized trained dog were evaluated. Microencapsulated beads were prepared which produced controlled release as assayed by bronchodilation. The heart rate increases induced by the controlled-release formulations were gradual in onset, and the total increase in heart rate over a 6-hr period was less than that associated with the plain drug powder.

[Animal production and animal health and their relationship with veterinary public health in Latin America and the Caribbean]. / La producción y la salud animal y sus interrelaciones con la salud pública veterinaria en América Latina y el Caribe.

The authors analyse the relationships which exist, in terms of programmes, sectors and institutions, between animal health, animal production and veterinary public health on the one hand, and between each of these three sectors and public health in general on the other. The most important common factor is food safety. Undernutrition, which affects some 60 million inhabitants of Latin America and the Caribbean, is still the most important public health problem in this part of the world. While it is known that the major cause of undernutrition is the low gross domestic product and uneven distribution of wealth, increased animal production and productivity would provide the key to an improvement in the situation. The concept of animal health, in its broadest sense, implies optimum animal production in a given region and during a specified period of time. Veterinary public health has functions and objectives which are crucial for food safety: protection and hygiene of foods, and control of the use in animal production of substances toxic to human beings (such as heavy metals, hormones and insecticides). Within the area of transmissible diseases, the authors discuss control measures for zoonoses. Besides the specific subject of interdisciplinary relationships in regard to zoonoses, the authors stress the importance of joint work conducted in the research, development and implementation of laboratory diagnostic activities and the production and quality control of antigens and vaccines. The production of laboratory animals is another sphere of common activity and research, and it cannot be said that such work is specific to any one of the three disciplines. Moreover, the fields of health, animal health and veterinary public health share the same methods and strategies, and reciprocal benefits could be more significant than the objectives of individual programmes. Reference is made to the organisation of state services and their adaptation to administrative de-centralisation, particularly at the local level.

Widespread cutaneous herpes simplex type II infection.

The case of an adult who survived a widespread culture-proven cutaneous herpes simplex type II infection is presented. The authors believe it is the first such case. The virus was demonstrated by its cytopathic effect in Vero cell culture. Large, swollen syncytial cells and holes in the cell sheet, typical of the changes produced by the herpes simplex virus type II, were noted. Photodynamic inactivation therapy with acriflavine dye and fluorescent light was employed.